Patterns of spinal sensory-motor connectivity prescribed by a dorsoventral positional template.

Sensory-motor circuits in the spinal cord are constructed with a fine specificity that coordinates motor behavior, but the mechanisms that direct sensory connections with their motor neuron partners remain unclear. The dorsoventral settling position of motor pools in the spinal cord is known to match the distal-to-proximal position of their muscle targets in the limb, but the significance of invariant motor neuron positioning is unknown. An analysis of sensory-motor connectivity patterns in FoxP1 mutant mice, where motor neuron position has been scrambled, shows that the final pattern of sensory-motor connections is initiated by the projection of sensory axons to discrete dorsoventral domains of the spinal cord without regard for motor neuron subtype or, indeed, the presence of motor neurons. By implication, the clustering and dorsoventral settling position of motor neuron pools serve as a determinant of the pattern of sensory input specificity and thus motor coordination.

Prospective effects of work-time control on overtime, work-life interference and exhaustion in female and male knowledge workers.

AIMS: Employee-based flexible working hours are increasing, particularly among knowledge workers. Research indicates that women and men use work-time control (WTC; control over time off and daily hours) differently: while men work longer paid hours, women use WTC to counteract work-life interference. In a knowledge-worker sample, we examined associations between WTC and overtime, work-life interference and exhaustion and tested whether gender moderates the mediating role of overtime. METHODS: The sample contained 2248 Swedish knowledge workers. Employing hierarchical regression modelling, we examined effects of control over time off/daily hours on subsequent overtime hours, work-life interference and exhaustion in general and in gender-stratified samples. Using conditional process analysis, we tested moderated mediation models. RESULTS: Control over time off was related to less work-life interference (ßmen= -0.117; 95% confidence interval (CI): -0.237 to 0.003; ßwomen= -0.253; 95% CI: -0.386 to -0.120) and lower exhaustion (ßmen= -0.199; 95% CI: -0.347 to -0.051; ßwomen= -0.271; 95% CI: -0.443 to -0.100). For control over daily hours, estimates were close to zero. While men worked more overtime (42 min/week), we could not confirm gender moderating the indirect effect of control over time off/daily hours on work-life interference/exhaustion via overtime. Independent of gender, effects of control over time off on work-life interference were partly explained by working fewer overtime hours. CONCLUSIONS: Control over time off was related to lower exhaustion and better work-life balance (in particular for women). We found no evidence for men's work-life interference increasing with higher WTC owing to working more overtime. Knowledge workers' control over time off may help prevent work-life interference and burnout.

Hox repertoires for motor neuron diversity and connectivity gated by a single accessory factor, FoxP1.

The precision with which motor neurons innervate target muscles depends on a regulatory network of Hox transcription factors that translates neuronal identity into patterns of connectivity. We show that a single transcription factor, FoxP1, coordinates motor neuron subtype identity and connectivity through its activity as a Hox accessory factor. FoxP1 is expressed in Hox-sensitive motor columns and acts as a dose-dependent determinant of columnar fate. Inactivation of Foxp1 abolishes the output of the motor neuron Hox network, reverting the spinal motor system to an ancestral state. The loss of FoxP1 also changes the pattern of motor neuron connectivity, and in the limb motor axons appear to select their trajectories and muscle targets at random. Our findings show that FoxP1 is a crucial determinant of motor neuron diversification and connectivity, and clarify how this Hox regulatory network controls the formation of a topographic neural map.

Randomised control trial of a proactive intervention supporting recovery in relation to stress and irregular work hours: effects on sleep, burn-out, fatigue and somatic symptoms.

OBJECTIVES: To examine if a proactive recovery intervention for newly graduated registered nurses (RNs) could prevent the development of sleep problems, burn-out, fatigue or somatic symptoms. METHODS: The study was a randomised control trial with parallel design. Newly graduated RNs with less than 12 months' work experience were eligible to participate. 461 RNs from 8 hospitals in Sweden were invited, of which 207 signed up. These were randomised to either intervention or control groups. After adjustments, 99 RNs were included in the intervention group (mean age 27.5 years, 84.7% women) and 108 in the control group (mean age 27.0 years, 90.7% women). 82 RNs in the intervention group attended a group-administered recovery programme, involving three group sessions with 2 weeks between each session, focusing on proactive strategies for sleep and recovery in relation to work stress and shift work. Effects on sleep, burn-out, fatigue and somatic symptoms were measured by questionnaires at baseline, postintervention and at 6 months follow-up. RESULTS: Preventive effect was seen on somatic symptoms for the intervention group. Also, the intervention group showed less burn-out and fatigue symptoms at postintervention. However, these latter effects did not persist at follow-up. Participants used many of the strategies from the programme. CONCLUSIONS: A proactive, group-administered recovery programme could be helpful in strengthening recovery and preventing negative health consequences for newly graduated RNs. TRIAL REGISTRATION NUMBER: NCT04246736.

Association of rotating shift work schedules and the use of prescribed sleep medication: A prospective cohort study.

We examined whether working rotating shifts, with or without night work, is associated with the purchase of prescribed sleep medication, and whether the association is dependent on age. Data were obtained from a longitudinal cohort study of Finnish public sector employees who responded to questions on work schedule and background characteristics in 2000, 2004 and 2008. The data were linked to national register data on redeemed prescriptions of hypnotic and sedative medications, with up to 11 years of follow-up. Age stratified Cox proportional hazard regression models were computed to examine incident use of medication comparing two groups of rotating shift workers (those working shifts that included night shifts and those whose schedules did not include night shifts) with day workers who worked in a similar range of occupations. Shift work with night shifts was associated with increased use of sleep medication in all age groups, after adjustments for sex, occupational status, marital status, alcohol consumption, smoking and physical activity levels (hazard ratio [HR], [95% confidence interval, CI] 1.14 [1.01-1.28] for age group ≤39 years; 1.33 [1.19-1.48] for age group 40-49 years; 1.28 [1.13-1.44] for age group ≥50 years). Shift work without nights was associated with medication use in the two older age groups (HR [95% CI] 1.14 [1.01-1.29] and 1.17 [1.05-1.31] for age groups 40-49 years and >50 years, respectively). These findings suggest that circadian disruption and older age puts rotating shift workers, and especially those who work nights, at increased risk of developing clinically significant levels of sleep problems.

Psychosocial working conditions of shiftworking nurses: A long-term latent transition analysis.

AIM: This study aimed to identify profiles of working conditions to which nurses were exposed to over time and investigate how changes in working conditions relate to shiftworking and health. BACKGROUND: Previous studies rarely addressed the issue of working conditions development over long periods and the effects of such development on nurses' health. METHODS: Data from a national cohort of nurses in Sweden (N = 2936) were analysed using a person-centred analytical approach-latent profile and latent transition analysis. RESULTS: Nurses report better psychosocial working conditions as they progress into mid-career. Shiftworking nurses experience poorer working conditions than their dayworking counterparts and tend to move from shiftwork to daywork as they progress into mid-career. In mid-career, nurses in work environments characterized by low autonomy and support tend to report poorer health outcomes. CONCLUSION: Current analyses suggest that shiftworking nurses are particularly in need of interventions that address poor work environments. Not only do they experience more negative psychosocial working conditions than their dayworking counterparts, but they do so while having to contend with demanding schedules. IMPLICATIONS FOR NURSING MANAGEMENT: The findings highlight that organisational interventions should target different aspects of the work environment for nurses in diverse stages of their careers.

Sleep and fatigue in newly graduated nurses-Experiences and strategies for handling shiftwork.

AIMS AND OBJECTIVES: To explore newly graduated nurses' strategies for, and experiences of, sleep problems and fatigue when starting shiftwork. A more comprehensive insight into nurses' strategies, sleep problems, fatigue experiences and contributing factors is needed to understand what support should be provided. BACKGROUND: For graduate nurses, the first years of practice are often stressful, with many reporting high levels of burnout symptoms. Usually, starting working as a nurse also means an introduction to shiftwork, which is related to sleep problems. Sleep problems may impair stress management and, at the same time, stress may cause sleep problems. Previously, sleep problems and fatigue have been associated with burnout, poor health and increased accident risk. DESIGN AND METHODS: Semi-structured interviews were conducted with nurses (N = 11) from four different Swedish hospitals, and qualitative inductive content analysis was used. The study was approved by the Regional Ethical Review Board in Stockholm. The COREQ checklist was followed. RESULTS: Many nurses lacked effective strategies for managing sleep and fatigue in relation to shiftwork. Various strategies were used, of which some might interfere with factors regulating and promoting sleep such as the homeostatic drive. Sleep problems were common during quick returns, often due to difficulties unwinding before sleep, and high workloads exacerbated the problems. The described consequences of fatigue in a clinical work context indicated impaired executive and nonexecutive cognitive function. CONCLUSION: The findings indicate that supporting strategies and behaviours for sleep and fatigue in an intervention for newly graduated nurses starting shiftwork may be of importance to improve well-being among nurses and increase patient safety. RELEVANCE TO CLINICAL PRACTICE: This study highlights the importance of addressing sleep and fatigue issues in nursing education and work introduction programmes to increase patient safety and improve well-being among nurses.

Investigating the factorial structure and availability of work time control in a representative sample of the Swedish working population.

AIMS: Past research has often neglected the sub-dimensions of work time control (WTC). Moreover, differences in levels of WTC with respect to work and demographic characteristics have not yet been examined in a representative sample. We investigated these matters in a recent sample of the Swedish working population. METHODS: The study was based on the 2014 data collection of the Swedish Longitudinal Occupational Survey of Health. We assessed the structure of the WTC measure using exploratory and confirmatory factor analysis. Differences in WTC by work and demographic characteristics were examined with independent samplet-tests, one-way ANOVAs and gender-stratified logistic regressions. RESULTS: Best model fit was found for a two-factor structure that distinguished between control over daily hours and control over time off (root mean square error of approximation = 0.06; 95% CI 0.04 to 0.09; Comparative Fit Index (CFI) = 0.99). Women, shift and public-sector workers reported lower control in relation to both factors. Age showed small associations with WTC, while a stronger link was suggested for civil status and family situation. Night, roster and rotating shift work seemed to be the most influential factors on reporting low control over daily hours and time off. CONCLUSIONS: Our data confirm the two-dimensional structure underlying WTC, namely the components 'control over daily hours' and 'control over time off'. Women, public-sector and shift workers reported lower levels of control. Future research should examine the public health implications of WTC, in particular whether increased control over daily hours and time off can reduce health problems associated with difficult working-time arrangements.

Systematic review of the relationship between quick returns in rotating shift work and health-related outcomes.

A systematic literature search was carried out to investigate the relationship between quick returns (i.e., 11.0 hours or less between two consecutive shifts) and outcome measures of health, sleep, functional ability and work-life balance. A total of 22 studies published in 21 articles were included. Three types of quick returns were differentiated (from evening to morning/day, night to evening, morning/day to night shifts) where sleep duration and sleepiness appeared to be differently affected depending on which shifts the quick returns occurred between. There were some indications of detrimental effects of quick returns on proximate problems (e.g., sleep, sleepiness and fatigue), although the evidence of associations with more chronic outcome measures (physical and mental health and work-life balance) was inconclusive. PRACTITIONER SUMMARY: Modern societies are dependent on people working shifts. This study systematically reviews literature on the consequences of quick returns (11.0 hours or less between two shifts). Quick returns have detrimental effects on acute health problems. However, the evidence regarding effects on chronic health is inconclusive.

Foxp1/4 control epithelial cell fate during lung development and regeneration through regulation of anterior gradient 2.

The molecular pathways regulating cell lineage determination and regeneration in epithelial tissues are poorly understood. The secretory epithelium of the lung is required for production of mucus to help protect the lung against environmental insults, including pathogens and pollution, that can lead to debilitating diseases such as asthma and chronic obstructive pulmonary disease. We show that the transcription factors Foxp1 and Foxp4 act cooperatively to regulate lung secretory epithelial cell fate and regeneration by directly restricting the goblet cell lineage program. Loss of Foxp1/4 in the developing lung and in postnatal secretory epithelium leads to ectopic activation of the goblet cell fate program, in part, through de-repression of the protein disulfide isomerase anterior gradient 2 (Agr2). Forced expression of Agr2 is sufficient to promote the goblet cell fate in the developing airway epithelium. Finally, in a model of lung secretory cell injury and regeneration, we show that loss of Foxp1/4 leads to catastrophic loss of airway epithelial regeneration due to default differentiation of secretory cells into the goblet cell lineage. These data demonstrate the importance of Foxp1/4 in restricting cell fate choices during development and regeneration, thereby providing the proper balance of functional epithelial lineages in the lung.

Chronic effects of shift work on cognition: findings from the VISAT longitudinal study.

OBJECTIVES: Shift work, like chronic jet lag, is known to disrupt workers' normal circadian rhythms and social life, and to be associated with increased health problems (eg, ulcers, cardiovascular disease, metabolic syndrome, breast cancer, reproductive difficulties) and with acute effects on safety and productivity. However, very little is known about the long-term consequences of shift work on cognitive abilities. The aim of this study was to assess the chronicity and reversibility of the effects of shift work on cognition. METHODS: We conducted a prospective cohort study of 3232 employed and retired workers (participation rate: 76%) who were 32, 42, 52 and 62 years old at the time of the first measurement (t1, 1996), and who were seen again 5 (t2) and 10 (t3) years later. 1484 of them had shift work experience at baseline (current or past) and 1635 had not. The main outcome measures were tests of speed and memory, assessed at all three measurement times. RESULTS: Shift work was associated with impaired cognition. The association was stronger for exposure durations exceeding 10 years (dose effect; cognitive loss equivalent to 6.5 years of age-related decline in the current cohort). The recovery of cognitive functioning after having left shift work took at least 5 years (reversibility). CONCLUSIONS: Shift work chronically impairs cognition, with potentially important safety consequences not only for the individuals concerned, but also for society.

Developmental and species-divergent globin switching are driven by BCL11A.

The contribution of changes in cis-regulatory elements or trans-acting factors to interspecies differences in gene expression is not well understood. The mammalian beta-globin loci have served as a model for gene regulation during development. Transgenic mice containing the human beta-globin locus, consisting of the linked embryonic (epsilon), fetal (gamma) and adult (beta) genes, have been used as a system to investigate the temporal switch from fetal to adult haemoglobin, as occurs in humans. Here we show that the human gamma-globin (HBG) genes in these mice behave as murine embryonic globin genes, revealing a limitation of the model and demonstrating that critical differences in the trans-acting milieu have arisen during mammalian evolution. We show that the expression of BCL11A, a repressor of human gamma-globin expression identified by genome-wide association studies, differs between mouse and human. Developmental silencing of the mouse embryonic globin and human gamma-globin genes fails to occur in mice in the absence of BCL11A. Thus, BCL11A is a critical mediator of species-divergent globin switching. By comparing the ontogeny of beta-globin gene regulation in mice and humans, we have shown that alterations in the expression of a trans-acting factor constitute a critical driver of gene expression changes during evolution.

Working hours and health - key research topics in the past and future.

OBJECTIVE: This paper discusses the past and present highlights of working hours and health research and identifies key research needs for the future. METHOD: We analyzed over 220 original articles and reviews on working hours and health in the Scandinavian Journal of Work, Environment & Health published during the last 50 years. Key publications from other journals were also included. RESULTS: The majority of identified articles focussed on the effects of shift and night work, with fewer studying long and reduced working hours and work time control. We observed a transition from small-scale experimental and intensive field studies to large-scale epidemiological studies utilizing precise exposure assessment, reflecting the recent emergence of register-based datasets and the development of analytic methods and alternative study designs for randomized controlled designs. The cumulative findings provide convincing evidence that shift work and long working hours, which are often associated with night work and insufficient recovery, increase the risk of poor sleep and fatigue, sickness absence, occupational injuries, and several chronic health conditions such as cardiovascular diseases and cancer. The observed risks are strongly modified by individual and work-related factors. CONCLUSIONS: Although the observed health risks of shift work and long working hours are mostly low or moderate, the widespread prevalence of exposure and the hazardousness of the many associated potential outcomes makes such working time arrangements major occupational health risks. Further research is needed to identify exposure-response associations, especially in relation to the chronic health effects, and to elucidate underlying pathways and effective personalized intervention strategies.

Quick returns, sleep, sleepiness and stress - An intra-individual field study on objective sleep and diary data.

OBJECTIVES: Quick returns (<11 hours of rest between shifts) have been associated with shortened sleep length and increased sleepiness, but previous efforts have failed to find effects on sleep quality or stress. A shortcoming of most previous research has been the reliance on subjective measures of sleep. The aim of this study was to combine diary and actigraphy data to investigate intra-individual differences in sleep length, sleep quality, sleepiness, and stress during quick returns compared to day-day transitions. METHODS: Of 225 nurses and assistant nurses who wore actigraphy wristbands and kept a diary of work and sleep for seven days, a subsample of 90 individuals with one observation of both a quick return and a control condition (day-day transition) was extracted. Sleep quality was assessed with actigraphy data on sleep fragmentation and subjective ratings of perceived sleep quality. Stress and sleepiness levels were rated every third hour throughout the day. Shifts were identified from self-reported working hours. Data was analyzed in multilevel models. RESULTS: Quick returns were associated with 1 hour shorter sleep length [95% confidence interval (CI) -1.23- -0.81], reduced subjective sleep quality (-0.49, 95% CI -0.69- -0.31), increased anxiety at bedtime (-0.38, 95% CI -0.69- -0.08) and increased worktime sleepiness (0.45, 95%CI 0.22- 0.71), compared to day-day transitions. Sleep fragmentation and stress ratings did not differ between conditions. CONCLUSIONS: The findings of impaired sleep and increased sleepiness highlight the need for caution when scheduling shift combinations with quick returns.

Signalling of the BCR is regulated by a lipid rafts-localised transcription factor, Bright.

Regulation of BCR signalling strength is crucial for B-cell development and function. Bright is a B-cell-restricted factor that complexes with Bruton's tyrosine kinase (Btk) and its substrate, transcription initiation factor-I (TFII-I), to activate immunoglobulin heavy chain gene transcription in the nucleus. Here we show that a palmitoylated pool of Bright is diverted to lipid rafts of resting B cells where it associates with signalosome components. After BCR ligation, Bright transiently interacts with sumoylation enzymes, blocks calcium flux and phosphorylation of Btk and TFII-I and is then discharged from lipid rafts as a Sumo-I-modified form. The resulting lipid raft concentration of Bright contributes to the signalling threshold of B cells, as their sensitivity to BCR stimulation decreases as the levels of Bright increase. Bright regulates signalling independent of its role in IgH transcription, as shown by specific dominant-negative titration of rafts-specific forms. This study identifies a BCR tuning mechanism in lipid rafts that is regulated by differential post-translational modification of a transcription factor with implications for B-cell tolerance and autoimmunity.

Regulation of RNA-polymerase-II-dependent transcription by N-WASP and its nuclear-binding partners.

The presence of actin in the nucleus has been well established, and several studies have implicated nuclear actin in transcriptional regulation. Neuronal Wiskott-Aldrich syndrome protein (N-WASP) is a member of the WASP family of proteins; these proteins function in the cytoplasm as key regulators of cortical actin filament. Interestingly, N-WASP has also been observed in the nucleus. However, a potential nuclear function for N-WASP has not been established. Here, we report the identification of nuclear N-WASP within a large nuclear-protein complex containing PSF-NonO (polypyrimidine-tract-binding-protein-associated splicing factor-non-Pou-domain octamer-binding protein/p54(nrb)), nuclear actin and RNA polymerase II. The PSF-NonO complex is involved in the regulation of many cellular processes, such as transcription, RNA processing, DNA unwinding and repair. We demonstrate that the interaction of N-WASP with the PSF-NonO complex can couple N-WASP with RNA polymerase II to regulate transcription. We also provide evidence that the potential function of N-WASP in promoting polymerization of nuclear actins has an important role in this process. Based on these results, we propose a nuclear function for N-WASP in transcriptional regulation.

Aglycosylated IgG variants expressed in bacteria that selectively bind FcgammaRI potentiate tumor cell killing by monocyte-dendritic cells.

The N-linked glycan of immunoglobulin G (IgG) is indispensable for the interaction of the Fc domain with Fcgamma receptors on effector cells and the clearance of target cells via antibody dependent cell-mediated cytotoxicity (ADCC). Escherichia coli expressed, aglycosylated Fc domains bind effector FcgammaRs poorly and cannot elicit ADCC. Using a novel bacterial display/flow cytometric library screening system we isolated Fc variants that bind to FcgammaRI (CD64) with nanomolar affinity. Binding was critically dependent on amino acid substitutions (E382V, and to a lesser extent, M428I) distal to the putative FcgammaRI binding epitope within the CH3 domain. These mutations did not adversely affect its pH-dependent interaction with FcRn in vitro nor its serum persistence in vivo. Remarkably, the anti-Her2 IgG trastuzumab containing the E382V, M428I substitutions and expressed in E. coli exhibited highly selective binding to FcgammaRI but not to the other activating receptors (FcgammaRIIa, FcgammaRIIIa) nor to the inhibitory receptor, FcgammaRIIb. In contrast, the glycosylated version of trastuzumab (E382V, M428I) purified from HEK293T cells bound to all Fcgamma receptors in a manner similar to that of clinical grade trastuzumab. E. coli-purified trastuzumab (E382V, M428I), but not glycosylated trastuzumab (E382V, M428I) or clinical grade trastuzumab, was capable of potentiating the killing of Her2 overexpressing tumor cells with dendritic cells (DCs) as effectors. These results indicate that aglycosylated IgGs can be engineered to display unique FcgammaR selectivity profiles that, in turn, mediate ADCC via mechanisms that are not normally displayed by glycosylated monoclonal antibodies.

Alexithymia and burnout in nursing students.

Although previous studies have indicated an association between alexithymia and burnout, they have not controlled for well-established organizational factors, depression, and coping mechanisms that could confound the relationship. This study investigated the association between alexithymia and occupational burnout. One hundred eighty-three nursing students were assessed up to 3 months before graduating from their program. Alexithymia was measured with the Toronto Alexithymia Scale, occupational burnout was measured with the Maslach Burnout Inventory, work-related factors were measured with the Areas of Worklife Survey, depression was measured with Beck Depression Inventory-II, and coping strategies were measured with the COPE Dispositional Inventory. Hierarchical multiple regressions indicated that externally oriented thinking style was significantly associated with personal accomplishment and depersonalization after adjusting for depression, coping, and work-related factors. The results indicate that only a single aspect of the alexithymia construct serves as a possibly independent predisposing factor for specific burnout dimensions.

Pros and cons of quick returns-a cross-sectional survey among Swedish nurses and nurse assistants.

Short rest (<11h) between evening and day shifts-known as quick returns (QRs)-impede recovery and may impair health. Nevertheless, QRs remain popular among some shift workers. This study explores nurses' and nurse assistants' perceptions of the merits and demerits of QRs from individual and organizational perspectives. Participants were recruited from eleven wards at two Swedish hospitals as part of a larger quasi-experimental intervention study. The majority (79%) had influence over their work schedules. Frequency distributions of responses are presented. Ninety six undertook a baseline survey regarding recovery, tolerance and work performance in relation to QRs. A majority experienced difficulties unwinding before bedtime (76%), insufficient sleep (80%), and daytime fatigue (72%). A third experienced an increased risk of errors and mistakes. However, QRs appeared to facilitate taking reports from patients and planning work, as this task was more often rated as 'very easy' following a QR compared to other shift combinations. Tolerance of QRs varied substantially. In conclusion, QRs seem to benefit continuity in work processes, but may do so at the expense of recovery and safety. Wards planning to reduce QRs-through participatory or fixed schedule models-should consider impacts on work processes.

Foxp1 is an essential transcriptional regulator for the generation of quiescent naive T cells during thymocyte development.

Proper thymocyte development is required to establish T-cell central tolerance and to generate naive T cells, both of which are essential for T-cell homeostasis and a functional immune system. Here we demonstrate that the loss of transcription factor Foxp1 results in the abnormal development of T cells. Instead of generating naive T cells, Foxp1-deficient single-positive thymocytes acquire an activated phenotype prematurely in the thymus and lead to the generation of peripheral CD4(+) T and CD8(+) T cells that exhibit an activated phenotype and increased apoptosis and readily produce cytokines upon T-cell receptor engagement. These results identify Foxp1 as an essential transcriptional regulator for thymocyte development and the generation of quiescent naive T cells.